Background: We have previously shown that metalloproteinase 7 (MMP7) expression is increased during the acquisition of resistance to oxaliplatin in colon cancer cells. Now we have analyzed the implication of β-catenin and EGFR pathways in the up-regulation of MMP7 in the oxaliplatin-resistant human colon cancer cell lines RHT29 and RHCT116 p53-/-, derived from the HT29 and HCT116 p53-/- cells, respectively. Results: Oxaliplatin treatment increased EGFR expression and induced its activation in all the cell lines. However, β-catenin mRNA was only upregulated in the HT29 and RHT29 cells, with a marked increase in the nuclear/cytoplasmic β-catenin protein ratio in the oxaliplatin-resistant RHT29 cells. To determine the contribution of β-catenin and EGFR to the expression of MMP7 we performed siRNA experiments. β-catenin abrogation only prevented the induction of MMP7 by oxaliplatin in HT29 and RHT29 cells. Accordingly, viability of oxaliplatin-treated RHT29 cells under β-catenin silencing was decreased. On the other hand, EGFR siRNA induced contradictory effects, decreasing PEA3 and MMP7 expression in control and oxaliplatin-treated RHCT116 p53-/- cells but increasing basal- and oxaliplatin-induced PEA3 and MMP7 in the HT29 and RHT29 cells. Conclusions: Oxaliplatin-induced MMP7 up-regulation is differentially achieved in colon cancer cell lines, as a result of EGFR and β-catenin cross-talk on MMP7 gene transcription. Taken together, our results point out the disparity of effects that β-catenin and EGFR blocking therapeutic strategies may exert on MMP7 expression depending on the cellular context and remark the importance of a better knowledge of MMP7 regulation to improve chemotherapy effectiveness in colon cancer.